ES2309594T3 - COMPOSITIONS CONTAINING BLOCKERS OF CALCIUM CHANNELS OF TYPE L AND INHIBITORS OF THE CHOLINESTERASE. - Google Patents

Abstract

The present invention relates to compositions at least one L-type calcium channel blocker, particularly the compound (+)-isopropyl 2-methoxyethyl 4-(2-chloro-3-cyano-phenyl)-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylate, in combination with at least one cholinesterase inhibitor, particularly donepezil, and uses thereof in methods of treatment.

Description

Compositions containing blockers of L-type calcium channels and cholinesterase inhibitors.

The present invention relates to compositions containing at least the calcium channel blocker type L, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl,  combined with at least the cholinesterase inhibitor, donepezil, and their uses in procedures therapeutic

Background of the invention

Meier et al. (U.S. Patent 5,665,740), whose description is incorporated in its entirety herein reference mode, they disclose that the compound 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl, it has a positive effect on learning ability and memory, as well as potential antidepressant.

The pathology of memory impairment is manifested by a deterioration in the ability to learn new information and / or the inability to remember information previously learned. Memory impairment is a symptom. main dementia and can also be a symptom associated with various diseases and conditions, such as the disease of Alzheimer's or cognitive decline related to age.

The present invention relates to compositions containing at least the calcium channel blocker type L, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl,  combined with at least cholinesterase inhibitor, donepezil, and their uses in procedures therapeutic, particularly in treatments of deterioration of the memory and / or cognitive.

Characteristics of the invention.

The present invention relates to a procedure for the treatment of memory impairment and / or cognitive impairment, consisting of administering to a patient (for example, a human), simultaneously or sequentially, a L-type calcium channel blocker and an inhibitor of cholinesterase In the procedures in which the simultaneous administration, agents can be presented in of a combined composition or they can be administered by separated. According to the invention, the calcium channel blocker  type L is 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl. According to the invention, the cholinesterase inhibitor is donepezil

For example, the compound 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl,  it can be administered in combination with the inhibitor of cholinesterase donepezil. In that combination, each principle asset will be administered either according to your usual dosage or either at a dose lower than the usual dosage range.

According to a further aspect, the invention is refers to a procedure for the treatment of deterioration of memory and / or cognitive associated with Alzheimer's disease, consisting of administering to a patient (for example, a human), simultaneously or sequentially, a blocker of the channels of L-type calcium and a cholinesterase inhibitor. In the procedures in which simultaneous administration is performed, the agents can be presented in the form of a combined composition or they can be administered separately. According to the invention, the L-type calcium channel blocker is 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl. According to another embodiment of this aspect of the invention, the inhibitor of cholinesterase is donepezil.

For example, the invention relates to procedures for the treatment of memory impairment and / or Cognitive associated with Alzheimer's disease, consisting of administer to a patient (for example, a human), so simultaneous or sequential, the compound 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and a cholinesterase inhibitor used in the treatment of Alzheimer's disease, such as Aricept (donepezil, specifically donepezil hydrochloride). In the proceedings in which simultaneous administration is performed, the agents they can be presented in the form of a combined composition or They can be administered separately.

According to a further aspect, the invention is refers to a procedure for the treatment of deterioration of the memory and / or cognitive associated with dementia, consisting of administer to a patient (for example, a human), so simultaneous or sequential, a calcium channel blocker of type L and a cholinesterase inhibitor. In the procedures in those who perform simultaneous administration, agents can presented in the form of a combined composition or they can be administered separately According to an embodiment of this aspect of the invention, the L-type calcium channel blocker is 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl. According to another embodiment of this aspect of the invention, the inhibitor of cholinesterase is donepezil.

       \ vskip1.000000 \ baselineskip
    

For example, the invention relates to procedures for the treatment of memory impairment and / or Cognitive associated with dementia, consisting of administering to a patient (for example, a human), simultaneously or sequential, the compound 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and a cholinesterase inhibitor used in the treatment of dementia, such as Aricept (donepezil, specifically hydrochloride of donepezil). In the procedures in which the simultaneous administration, agents can be presented in of a combined composition or they can be administered by separated.

According to a further aspect, the invention is refers to a procedure for the treatment of deterioration of the memory and / or cognitive, consisting of administering to a patient (for example, a human), simultaneously or sequentially, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl  and donepezil (eg hydrochloride (+/-) - 2,3-dihydro-5,6-dimethoxy-2 - [[1- (phenylmethyl) -4-piperidinyl] methyl] -1H-inden-1-one).  In the procedures in which the administration is performed Simultaneously, agents can be presented in the form of a Combined composition or they can be administered separately.

According to a further aspect, the invention is refers to a procedure for the treatment of deterioration of the memory and / or cognitive associated with Alzheimer's disease, consisting of administering to a patient (for example, a human), simultaneously or sequentially, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and donepezil. In the procedures in which the simultaneous administration, agents can be presented in of a combined composition or they can be administered by separated.

According to a further aspect, the invention is refers to a procedure for the treatment of deterioration of the memory and / or cognitive associated with dementia, consisting of administer to a patient (for example, a human), so simultaneous or sequential, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and donepezil. In the procedures in which the simultaneous administration, agents can be presented in of a combined composition or they can be administered by separated.

Meier (and others) (U.S. Patent 5,665,740), give to know that 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl It can be used for: the treatment of degenerative disorders central such as those observed, for example, in dementias (multiinhartic dementia or DMI, primary degenerative dementia or PDD, presenile and senile Alzheimer's disease, HIV dementia and other forms of dementia), Parkinson's disease or sclerosis amyotrophic lateral; treatment of function disorders brain in old age, organic brain syndrome (SCO) and memory impairment associated with age (AMD); prophylaxis and the control of the sequelae of circulatory disorders brain, such as cerebral ischemia, stroke and hemorrhage subarachnoid; the treatment of depressions and manias; he migraine treatment; the treatment of neuropathies, caused, for example, by metabolic disorders such as diabetes mellitus, trauma, poisoning, microorganisms or autoimmune disorders; the treatment of addictive disorders; and treatment of withdrawal symptoms.

According to a further aspect of this invention, the combination of a calcium channel blocker type L and of a cholinesterase inhibitor can also be used to the treatments mentioned above, disclosed in the U.S.A. 5,665,740. According to this invention, the blocker of the type L calcium channels is 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl.  According to another embodiment of this aspect of the invention, the Cholinesterase inhibitor is donepezil. The blocker of type L calcium channels is 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and the cholinesterase inhibitor can be Aricept (donepezil, specifically donepezil hydrochloride).

The dosage of the compounds of the present invention depends on various factors, including the particular syndrome that you want to treat, the severity of symptoms, route of administration, interval frequency dosage, the particular compound used, the effectiveness, the toxicological profile and the pharmacokinetic profile of the compound as well such as the presence of any harmful side effects, between Other considerations.

According to the invention, the treatment combined with the calcium channel blocker type L, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and the donepezil acetylcholinesterase inhibitor gets strong results regarding the treatment of deterioration of Memory and / or cognitive. See example 1 described more ahead.

The compound 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl  it can be administered in an amount of, for example, 10-360 mg / day (e.g., 30 mg, 60 mg, or 120 mg two times a day). Donepezil is usually given in an amount 5-20 mg / day (usually the dose of Donepezil is adjusted to a tolerable level, but not greater than 20 mg / day).

However, as a result of the synergy, of according to the invention, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  of isopropyl-2-methoxyethyl and Donepezil can be administered, each of them, in an amount that is within the general intervals mentioned or in smaller quantities. So that, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  of isopropyl-2-methoxyethyl can be administer in an amount of 10-360 mg / day, while donepezil can be administered in an amount less than 5 mg / day (e.g., 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5,  4.0 or 4.5 mg). Alternatively, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  of isopropyl-2-methoxyethyl can be administered in an amount less than 10 mg / day, (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0 or 9.0 mg), while donepezil is administered in amounts of 5-20 mg / day Further, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate of isopropyl-2-methoxyethyl can be administered in an amount less than 10 mg / day, (e.g., 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0, 7.0, 8.0 or 9.0 mg), Y Donepezil can be administered in an amount less than 5 mg / day,  (e.g., 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0 or 4.5 mg). Alternatively, also according to the invention, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate of isopropyl-2-methoxyethyl can be administer in an amount of 10-360 mg / day, while donepezil is administered in an amount of 5-20 mg / day

The weight ratio between the quantity administered daily from 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  of isopropyl-2-methoxyethyl and the daily amount of donepezil is found comprised, for example, between 5: 1 and 30: 1, preferably between 15: 1 and 25: 1, for example, 10: 1, 12: 1, 14: 1, 16: 1, 17: 1, 18: 1, 19: 1, 21: 1, 22: 1, 23: 1, 24: 1, 27: 1 and 29: 1.

Among the side effects of donepezil are include nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue and anorexia Thus, donepezil is administered preferably in an amount less than 5 mg / day, while 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate of isopropyl-2-methoxyethyl can be preferably administered in an amount of 10-360 mg / day, or less than 10 mg.

The donepezil and the 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate of isopropyl-2-methoxyethyl se can be administered simultaneously or sequentially, in combined or independent compositions. Mode Administration can be any of those described above. However, oral administration is preferred, the administration by transdermal route and administration by route rectal, especially oral administration.

The compound of the invention can be administer alone or as active ingredient of a formulation. So thus, the present invention also includes the compositions pharmaceuticals of the compound of the invention, which contain, by example, one or more pharmaceutically acceptable excipients, and / or one or more active components.

Thus, according to an additional aspect, the invention includes a pharmaceutical composition containing a L-type calcium channel blocker and an inhibitor of cholinesterase The type L calcium channel blocker is 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl.  In addition, the cholinesterase inhibitor is donepezil.

In the pharmaceutical composition, the relationship in Weight between 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and donepezil is between 5: 1 and 30: 1, preferably between 15: 1 and 25: 1. The compositions may, for example, contain 10-360 mg of 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and 5-20 mg of donepezil. Alternatively, the compositions may, for example, contain less than 10 mg of 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl  and 5-20 mg of donepezil, or 10-360 mg of 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and less than 5 mg of donepezil, or less than 10 mg of 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and less than 5 mg of donepezil.

There are numerous standardized references that describe the procedures for preparing various formulations suitable for administration of the compound according to the invention. In the Handbook of Pharmaceutical Excipients publication, American Pharmaceutical Association (current edition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman and Schwartz, editors) current edition, published by Marcel Dekker, Inc., as well as Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current edition), examples of Possible formulations and preparations.

Administration can be performed according to patient needs, for example, orally, nasally, parenteral (subcutaneous, intravenous, intramuscular, intrasternal and by infusion), rectal, vaginal, topical and by ocular administration.

Various solid forms can be used by oral route for administration mention compounds, including solid forms such as tablets, gel capsules, capsules, oblong tablets, granules, pills and bulk powder. The Compounds of the present invention can be administered alone or combined with various vehicles, diluents (such as sucrose, mannitol, lactose, starches) and pharmaceutically excipients acceptable known in the art, including but not limited to suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, dyes, aromas, lubricants, and Similar. They are also advantageous in the administration of Compounds of the present invention capsules, tablets and controlled release gels.

Similarly, you can use various Oral liquid forms for the administration of compounds of the invention, including aqueous solutions and not aqueous, emulsions, suspensions, syrups and elixirs. These administration forms may also contain inert diluents suitable known in the art, such as water and excipients suitable known in the art, such as preservatives, humectants, sweeteners, aromas, as well as emulsifiers and / or suspending agents of the compounds of the invention. The Compounds of the present invention can be injected, by for example, intravenously, in the form of a sterile solution isotonic It is also possible to make other preparations.

Suppositories can be prepared for rectal administration of the compounds herein invention, mixing the compounds with a suitable excipient, such like coconut butter, salicylates and polyethylene glycols. The Formulations for vaginal administration may be presented in pessary shape, buffer, cream, gel, paste, foam, or spray formulations, which contain, in addition to active ingredient, suitable excipients such as those known in the technique.

For topical administration, the composition Pharmaceutical can come in the form of creams, ointments liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, spray formulations and suitable drops for administration to the skin, eyes, ears or nose. The topical administration can also be done transdermally by, for example, transdermal patches.

The dosage of the compounds of the present invention depends on various factors, including the particular syndrome that you want to treat, the severity of symptoms, route of administration, interval frequency dosage, the particular compound used, the effectiveness, the toxicological profile and the pharmacokinetic profile of the compound as well such as the presence of any harmful side effects, between Other considerations.

Active components must be present in these preparations in a concentration between 0.1 and 99.5% by weight, preferably between 0.5 and 95% by weight of the mixture total. In general, it has been advantageous to administer the active components in total amounts between 0.01 and 50 mg / kg, approximately preferably in total amounts between 0.1 mg / kg and approximately 10 mg / kg body weight every 24 hours, if appropriate in the form of several individual doses, to In order to achieve the desired result.

A person with normal experience in the field will recognize that the compound 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  of isopropyl-2-methoxyethyl has a asymmetric carbon and therefore is able to exist in form of optical isomers, as well as in the form of racemic mixtures or not racemic of them. All these compounds, including racemates, non-racemic mixtures of enantiomers, pure enantiomers and substantially pure, are within the scope of the present invention Substantially pure enantiomers contain  no more than 5% w / w of the corresponding opposite enantiomer, preferably not more than 2%, and most preferably not more than one%.

Racemic compounds can be synthesized by various procedures, for example, as described in U.S.A. 5,665,740. For example, you can react 2-chloro-3-cyanobenzaldehyde with 2-methoxyethyl acetoacetate to obtain 2-acetyl-3- (2-chloro-3-cyano) -2-propenoate of 2-methoxyethyl. Subsequently, this compound is makes react with isopropyl amino-2-butenoate for obtain 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  of isopropyl-2-methoxyethyl racemic (See examples I and 1 of U.S.A. 5,665,740.) The compound 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl It can be obtained by subjecting the racemate to chiral chromatography. (See example 2 of U.S. Patent 5,665,740.)

The optical isomers can be obtained by resolution of racemic mixtures according to procedures conventional, for example, by salt formation diastereoisomerics using an acid or base optically assets or the formation of covalent diastereomers. As examples of suitable acids are tartaric acid, diacetyltartaric, dibenzoyltartaric, ditholuoyltartaric and camforsulfonic. Mixtures of diastereoisomers can be separate into their individual diastereomers based on their physical and / or chemical differences by known procedures by those skilled in the art, for example, by chromatography or fractional crystallization. Next, the bases or acids optically active are released from diastereomeric salts separated. A different procedure for the separation of optical isomers consists of the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional bypass, optimally chosen to maximize the separation of enantiomers Suitable chiral HPLC columns are those manufactured by, among many others, Diacel, eg, Chiracel OD and Chiracel OJ, all routinely selectable. Too Enzymatic separations are useful, with or without derivation. The optically active compounds of the intention can be obtained likewise using optically active starting materials in chiral synthesis procedures under reaction conditions that Do not cause racemization.

In addition, a person with normal experience in the matter will recognize that the compounds can be used in various enriched isotopic forms, that is, enriched in the content of 2 H, 3 H, 11 C, 13 C and / or 14 C. In A particular embodiment, the compounds are deuterated. Such deuterated forms can be synthesized by procedures described in U.S.A. No. 5,846,514 and 6,334,997, both incorporated herein by reference. According to described in U.S.A. No. 5,846,514 and 6,334,997, the deuteration can improve efficiency and increase the duration of The action of drugs.

Deuterium substituted compounds may synthesized by various procedures, such as described in the publications: Dean, Dennis C .; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6 (10)] (2000), 110 pp. CAN 133: 68895 AN 2000: 473538 CAPLUS; Kabalka, George W .; Varma, Rajender S. The synthesis of radiolabeled compounds VIA organometallic intermediates Tetrahedron (1989), 45 (21), 6601-21, CODE: TETRAB ISSN: 0040-4020. CAN 112: 20527 AN 1990: 20527 CAPLUS; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal Chem. (1981), 64 (1-2), 9-32. CODE: JRACBN ISSN: 0022-4081, CAN 95: 76229 AN 1981: 476229 CAPLUS, each of which is incorporates in the present invention by way of reference.

In the description above and in the examples following, all temperatures are indicated in degrees Celsius without correct and, unless otherwise indicated, all parties and percentages are expressed by weight.

Brief description of the drawings

Other various features, and advantages of the This invention will become more evident after considering the description in conjunction with the attached figures, in which:

Figure 1 illustrates the response data to the dose of compound A, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl, in the New Object Recognition Memory Test.

Figure 2 illustrates the response data to the Donepezil dose in the Recognition Memory Test New objects;

Figure 3 presents comparative data for the compound A alone, donepezil alone, memantine alone, the combination of memantine and donepezil the combination of compound A and Donepezil in the Object Recognition Memory Test New; Y

Figure 4 illustrates the response data to the Memantine dose in the Recognition Memory Test Objects - New;

Examples Example 1 Evaluation of the co-administration of donepezil and 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl in the New Object Recognition Report

The procedure is described below. General evaluation of compounds in the Annual Report New Object Recognition (non-spatial memory task hippocampus dependent):

1. Animals are transported in their cages originals from the hatchery to a training room with little lighting (5-6 lux) and acclimatize for about 45 minutes

2. Animals are placed individually in a training / testing environment (an opaque plastic chamber, of 61 cm x 42 cm x 37 cm with a bed on the floor) for 5 minutes of habituation Subsequently, the animals are returned to their cage original. They remained in the test room for about 15 minutes after the last animal is habituated, after what They return to their waiting room.

3. For the memory test, the objects that they must be differentiated are a cup (11 cm high, 6.5 cm high diameter) and a conical candle holder (11 cm high, 6 cm high diameter) made of non-transparent green glass. Are used Multiple copies of each object for training and testing. Object pairs are randomly assigned in each of the experiments For training, two objects are placed identical to 8 cm from the sides of the two short walls of the camera.

4. The day after the initial habituation, the Animals are returned to the testing room and acclimatized as described in step 1. Next, the drug is administered and / or the vehicle according to an experimental design (i.p .: gauge needle 26 3/8; or p.o .: 18 gauge needle) at an interval between 24 hours before and 24 hours after training. He training procedure begins by placing the animal, with the snout looking towards the wall, in the empty chamber in a position in The center of the long wall. After 1 minute of rehab, the animal is removed from the chamber and placed in a waiting cage (45 cm x 26 cm x 20 cm) with bed for 10 seconds. During this period, training objects are placed in the chamber. Next, the animal is returned to the chamber for a period 15 minute scan. The movements of the animal using a video camera located on the camera and it recorded on a videotape. After the training session, The animal is returned to its original cage. The objects are cleaned with an 85% EtOH solution. The animals remain in the room of tests for about 15 minutes after training last animal, after which they are returned to their waiting room.

5. After a delay interval (between 1 hour and several weeks, but usually 24 hours), the animals are they are placed back in the test room and acclimatized as described in step 1. After that, each animal is get back to the empty chamber for 1 minute, as described in step 4. For the test, two are placed in the chamber new objects: one is identical to the objects used during the training, while the other is new. For each animal, it randomize the position of the new object. The animals are allowed actively explore until they accumulate a total of 60 seconds of exploration. During the trial period, the time is recorded dedicated to exploring the new object or the familiar object through the R.E. Clark's V.P.C., which also points to the moment in the 60 seconds of scanning have elapsed. The animal movements using a video camera located on the camera and recorded on a videotape. It is excluded from analysis to any animal that does not explore any of the objects or that does not meet the criteria set within 15 minutes. After the test, the animals are returned to their original cage and then To your waiting room. The objects are cleaned with an EtOH solution 85%

6. Figures 1 and 2 represent the data. dose response for compound A and donepezil, respectively, in the Recognition Memory test of New objects The data shows that the dose approximately Optimum of compound A is 10 mg / kg, while the dose approximately optimal of donepezil is 0.5 mg / kg.

Intraperitoneal injections of donepezil (at the dose of 0.05 mg / kg; suboptimal dose of approximately 1/10 of the optimal dose) alone, 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl [hereinafter compound A] (at the dose of 1.00 mg / kg; dose suboptimal of approximately 1/10 of the optimal dose) alone, and co-administrations of donepezil (at the dose of 0.05 mg / kg; dose suboptimal approximately 1/10 of the optimal dose) and compound A (at the dose of 1.00 mg / kg; suboptimal dose of approximately 1/10 of the optimal dose) in the improved memory test of recognition of new objects in rats Young adult male Sprague-Dawley (3 months of age) (provided by Hilltop Lab Animals, Scottdale, PA), with a approximate weight between 350 and 450 grams.

The vehicle is 10% Cremophor in 0.9% NaCl; 20% EtOH, 60% PEG 400 and 20% H2O. Formulations contain 0.05 mg / ml donepezil in the vehicle; and 1.00 mg / ml of compound A in the vehicle. Total doses are 0.05 mg / kg and 1.00 mg / kg, respectively.

Rats are divided into four groups that They receive the following two injections:

Group 1) vehicle + vehicle;

Group 2) donepezil + vehicle;

Group 3) vehicle + compound A;

Group 4) donepezil + compound A;

All rats receive two injections i.p .: the First indication of the first component is administered 60 minutes after training, while the second injection of second component is administered 30 minutes after training.

The data is analyzed by an ANOVA followed by a post-hoc Tukey-Kramer test. Rats that receive vehicle-vehicle, donepezil-vehicle, and vehicle-compound A (n = 6 per group) explore both new and familiar objects (seen above) equally during the 24-hour test period after training, which indicates that these animals do not remember the familiar object.

On the contrary, the rats that receive both donepezil, 0.05 mg / kg as compound A, 1.00 mg / kg before training (n = 6) spend significantly more time (% Scan >> 50%) exploring the new object, which indicates A strong memory of the familiar object. This is surprising, since the individual suboptimal doses of donepezil, a acetylcholinesterase inhibitor, and compound A, a Calcium channel blocker type L, are not effective. All data is collected in Figure 3.

In addition, donepezil, an inhibitor of acetylcholinesterase, is evaluated in combination with the blocker of NMDA-R memantine receptors, just as the one described Figure 4 shows the response data to the memantine dose in the recognition memory test of new objects The data shows that the approximate optimal dose of memantine is 1.0 mg / kg. In figure 3 the data are presented corresponding to the suboptimal dose combination of 0.05 mg / kg of donepezil and the suboptimal dose of 0.3 mg / kg of memantine. While the data reveal a slight improvement in% scan compared to controls, vehicle-vehicle,  donepezilo-vehicle, and vehicle-memantine, the improvement is much smaller than the observed with the donepezil-compound combination TO.

Memantine and compound A works by Different mechanisms Memantine is a blocker of NMDA-R receptors, while compound A is a Calcium channel blocker type L. Similarly, the Donepezil is an acetylcholinesterase inhibitor and, by consequently, it acts through a mechanism different from that of memantine and compound A.

The above examples can be repeated with similar success replacing reagents and / or operating conditions of this invention generic or specifically described by the used in the previous examples.

Claims (8)

1. Use of a channel blocker of type L calcium for the production of a medicine for treatment of memory and / or cognitive impairment, where the L-type calcium channel blocker is 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl  and where the blocker administration pattern of L-type calcium channels consists of administration simultaneous or sequential with a cholinesterase inhibitor, in where said cholinesterase inhibitor is donepezil. 2. Use according to claim 1 in where cholinesterase inhibitor is present in a formulation combined with the calcium channel blocker of type L. 3. Use, according to any of the claims 1 or 2, wherein said memory impairment and / or Cognitive is associated with Alzheimer's disease. 4. Use, according to any of the claims 1 or 2, wherein said memory impairment and / or Cognitive is associated with dementia. 5. Pharmaceutical composition containing a L-type calcium channel blocker and an inhibitor of cholinesterase, where the calcium channel blocker of type L is 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and wherein said cholinesterase inhibitor is donepezil. 6. Pharmaceutical composition, according to claim 5, wherein the weight ratio between 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and donepezil is between 5: 1 and 30: 1. 7. Pharmaceutical composition, according to claim 5, wherein the weight ratio between 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate  from (+) - isopropyl-2-methoxyethyl and donepezil is between 15: 1 and 25: 1. 8. Pharmaceutical composition, according to one of the claims 5 to 7, wherein said composition contains 10-360 mg of 4- (2-Chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridin-3,5-dicarboxylate from (+) - isopropyl-2-methoxyethyl and 5-20 mg of donepezil.